1Universitätsklinikum Regensburg Innere Medizin II Regensburg, Deutschland; 2Universitätsklinikum Gießen und Marburg GmbH Gießen, Deutschland; 3Universitätsklinikum Gießen und Marburg GmbH Medizinische Klinik I - Kardiologie und Angiologie Gießen, Deutschland; 4Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; 5Herz- und Diabeteszentrum NRW Klinik für Thorax- und Kardiovaskularchirurgie Bad Oeynhausen, Deutschland; 6Universitätsklinikum Regensburg Klinik und Poliklinik für Innere Med. II, Kardiologie Regensburg, Deutschland; 7Universitätsklinikum Würzburg Institut für Pharmakologie und Toxikologie Würzburg, Deutschland
Introduction: Atrial fibrillation (AF) often coexists with heart failure (HF) but their interaction remains poorly understood. Clinical studies involving patients with AF and HF revealed improved left ventricular (LV) function following rhythm restoration, however, the underlying mechanisms remain unclear. This study investigated effects of AF and its termination in human LV myocardium as well as potential molecular mechanisms involved in the AF-induced remodeling.
Methods and Results: Human LV tissue slices from end-stage HF patients were long-term cultivated in-vitro. AF was simulated by tachy-arrhythmic culture pacing at 100 bpm with 30% beat-to-beat irregularity for 7 days and contractile LV function was compared to slices undergoing sinus rhythm (SR)-simulation (60 bpm/0%).
AF simulation resulted in a progressive decline in systolic force in human LV myocardium with a significantly reduced twitch amplitude compared to SR. Rhythm restoration was simulated by switching from AF to SR simulation after 7 days. Within just 5 days of AF termination, a significant improvement in LV function was observed, indicated by recovered systolic contraction amplitudes (Figure 1).
To elucidate cellular mechanisms of AF-induced LV dysfunction, human iPSC-cardiomyocytes (iPSC-CM) were subjected to the same AF simulation protocol used in human tissue slices. Epifluorescence microscopy measurements using Fura-2 staining revealed a significant reduction in systolic Ca2+ transient amplitudes after 7 days of AF simulation compared to the control. However, after 5 days of SR following AF simulation, iPSC-CM exhibited no difference in Ca2+ transient amplitude anymore, indicating a fast recovery of systolic Ca2+ cycling. As an underlying mechanism of systolic Ca2+ transient regulation we identified an increased diastolic Ca2+ release after 7 days of AF simulation compared to control in confocal microscopy line-scans (Fluo-4), which was subsequently reversed after 5 days of SR in iPSC-CM. These mechanisms could potentially explain the contractile response to AF in human myocardium.
To investigate the impact of reactive ROS on human cardiomyocytes, iPSC-CM were subjected to treatment with the ROS-scavenger N-acetylcysteine (NAC). After 7 days of AF simulation, Ca2+ transient amplitude was preserved in iPSC-CM after AF-simulation when treated with NAC, suggesting an interplay of ROS with the Ca2+ homeostasis of cardiomyocytes.Conclusion: This study demonstrates that AF per se impairs human contractile function of human end-stage LV myocardium. However, the involved changes in cardiomyocyte Ca2+ handling are reversible upon AF termination leading to improved LV function already within few days after AF cessation. Moreover, we provided an indication for an interplay of ROS with the Ca2+ homeostasis, endorsing an AF-induced LV-dysfunction. Identification of these mechanisms may further help to treat contractile dysfunction in patients with HF and permanent AF.